Search for alpha-helical propensity in the receptor-bound conformation of glucagon-like peptide-1.
To elucidate the receptor-bound conformation of glucagon-like peptide-1 (GLP-1), a series of conformationally constrained GLP-1 analogues were synthesized by introducing lactam bridges between Lys(i) and Glu(i)(+4) to form alpha-helices at various positions. The activity and affinity of these analogues to GLP-1 receptors suggested that the receptor-bound conformation comprises two alpha-helical segments between residues 11-21 and 23-34. It is notable that the N-terminal alpha-helix is extended to Thr(11), and that Gly(22) plays a pivotal role in arranging the two alpha-helices. Based on these findings, a highly potent bicyclic GLP-1 analogue was synthesized which is the most conformationally constrained GLP-1 analogue reported to date.
Murage
Eunice N
EN
Department of Chemistry, University of Texas at Dallas, Richardson, TX 75080, USA.
Schroeder
Jonathan C
JC
Beinborn
Martin
M
Ahn
Jung-Mo
JM
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D002942:Circular Dichroism; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D010456:Peptides, Cyclic; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1